CETP inhibitors are effective to inhibit the transfer of cholesteryl ester from HDL to LDL or to VLDL, thereby increasing HDL cholesterol that tends to prevent arteriosclerosis while lowering LDL cholesterol that tends to promote arteriosclerosis, and therefore expected to provide a useful new medical means as a preventive and/or therapeutic agent for arteriosclerotic diseases, hyperlipidemia or dyslipidemia.
And optically active tetrahydroquinoline derivatives are known as CETP inhibitors. See, WO 00/17164, WO 00/17165, WO 00/17166, WO 2006/012093 and WO 2005/095409.
Many of the tetrahydroquinoline derivatives described in the patent literatures above have a common structure of (2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl-amine as shown in the formula of I-a:
and the compound I-a is considered to be useful as a synthetic intermediate of the optically active tetrahydroquinoline derivatives described above.
Typical methods for preparing the tetrahydroquinoline derivatives are described, for example, in the patent literatures above. For example, optical resolution (Tokkyo Kokai 2001-163859), asymmetric synthesis WO02/088069, and asymmetric synthesis using a ruthenium catalyst (WO2004/074255) are described as a method for preparing optically active tetrahydroquinoline derivatives.
In the methods of preparing optically active tetrahydroquinoline derivatives, there were difficulties due to optical resolution and/or introductions and cleavages of protecting groups. Specifically, an optical resolution is required in a step of preparing the objective compound from 2-ethyl-4-amino-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline-1-carboxylic acid ethyl ester as shown in the reaction scheme of the patent literature (Tokkyo Kokai 2001-163859).
Moreover, an introduction and cleavage of a protecting group is required in a step of asymmetrical preparation of 4-[acetyl-(3,5-dimethylbenzyl)amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester from (R)-3-(4-trifluoromethyl-phenylamino)-pentanecarboxylic acid amide as shown in the reaction scheme B of WO 02/088069.
Furthermore, an expensive ruthenium catalyst is required in a step of preparing a compound (5)
wherein the symbols have the same meaning as defined in WO 2004/074255, by asymmetric reduction of a compound (4)
wherein the symbols have the same meaning as defined in WO 2004/074255, and a less expensive process is still desired.
A tetrahydroquinolin-4-one derivative having a similar chemical structure to the compound I-a may be prepared by a cyclization reaction of 3-(2-iodophenylamino)-propionic acid with phosphorus pentoxide, but it could not be prepared with polyphosphoric acid (J. Med. Chem., 47(22), 5467-5481 (2004)). In a case of 4-(4-trifluoromethylphenyl)butyric acid having the trifluoromethyl group at para position of the phenyl ring, however, the similar cyclization reaction did not proceed under the same condition (Tetrahedron Lett., 44, 4007-4010 (2003)).
As a process for preparing a racemate of the compound I-a, WO 00/17164 discloses preparation of a compound V
wherein the symbols have the same meaning as defined in WO 00/17164, by reduction of an oxime compound XIII
wherein the symbols have the same meaning as defined in WO 00/17164, using Ni—Al alloy. However, a reaction condition of stereoselective reduction is not described.
Additionally, it is known that the tetrahydroquinoline derivative having a similar chemical structure to the compound I-a may be prepared by cyclization reaction of propylidene-(4-trifluoromethyl-phenyl)-amine with a protected vinyl amine as shown in a patent literature (WO 00/17164, Example 7B) and a literature (Organic Process Research & Development 2006, 10, 464-471, Scheme 2). However, a resolution procedure is required at the final step to obtain the optically active tetrahydroquinoline derivative since the cyclization reaction afford a racemic product, and the yield of the optically active tetrahydroquinoline derivative is not satisfactory.